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Recombinant human erythropoietin in the anemia associated with multiple
myeloma or non-Hodgkin's lymphoma: dose finding and identification of
predictors of response
M Cazzola, D Messinger, V Battistel, D Bron, R Cimino, L Enller-Ziegler, U Essers, R Greil, A Grossi and G Jager
Department of Internal Medicine, University of Pavia, Italy.
Previous phase I-II clinical trials have shown that recombinant human
erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with
multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we
performed a randomized controlled multicenter study to define the optimal
initial dosage and to identify predictors of response to rHuEpo. A total of
146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had
no need for transfusion at the time of enrollment entered this trial.
Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29),
5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8
weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from
MM and 62 from low- to intermediate- grade NHL, including chronic
lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the
study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum
Epo level was 32 mU/mL, and endogenous Epo production was found to be
defective in 77% of the patients, as judged by a value for the ratio of
observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An
intention-to-treat analysis was performed to evaluate treatment efficacy.
The median average increase in Hb levels per week was 0.04 g/dL in the
control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58
(P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups,
respectively (P values versus control). The probability of response (delta
Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31%
(2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression
analysis using Cox's proportional hazard model and classification and
regression tree analysis showed that serum Epo levels and the O/P ratio
were the most important factors predicting response in patients receiving
5,000 or 10,000 U. Approximately three quarters of patients presenting with
Epo levels inappropriately low for the degree of anemia responded to
rHuEpo, whereas only one quarter of those with adequate Epo levels did so.
Classification and regression tree analysis also showed that doses of 2,000
U daily were effective in patients with an average platelet count greater
than 150 x 10(9)/L. About 50% of these patients are expected to respond to
rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of
MM and NHL patients who showed defective endogenous Epo production. From a
practical point of view, we conclude that the decision to use rHuEpo in an
individual anemic patient with MM or NHL should be based on serum Epo
levels, whereas the choice of the initial dosage should be based on
residual marrow function.
Volume 86,
Issue 12,
pp. 4446-4453,
12/15/1995
Copyright © 1995 by The American Society of Hematology
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